Pulmonary arterial hypertension (PAH) is a debilitating and deadly disease of the pulmonary circulation; although relatively rare, PAH affects persons of every ethnic group, race, gender, and age, including newborns. Current anti-PAH medications (prostacyclin analogs, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors) require cumbersome intravenous and subcutaneous injections, lack pulmonary selectivity, suffer from instability, produce systemic side effects, and fail to cur the underlying cause of the disease. Because PAH pathophysiology is entwined with multiple cellular and molecular pathways, single-drug therapy only modestly improves pulmonary hemodynamics and fails to restrain disease progression. Various combinations of anti-PAH drugs have recently been studied, but patient outcomes remain disappointing. Being predominantly vasodilators, the currently approved drugs do not reverse pulmonary vascular remodeling and abate right heart dysfunction, a major cause of deaths in PAH. We propose to circumvent indwelling catheter- and needle-based administration of drugs, intensify pulmonary selectivity, and reverse the pathogenesis of the disease to improve patient outcomes by formulating a combination of two drugs in nanocarriers equipped with a pulmonary homing device. We hypothesize that inhalable and targetable nanoparticles containing a vasodilator and an antioxidant will ameliorate pulmonary vasoconstriction, reverse pulmonary arterial remodeling, and abate right heart enlargement and failure in PAH. We will test this hypothesis by developing a targetable nanocarrier-based combination therapy that will simultaneously target two pathways of PAH pathogenesis: oxidative stress and Rho-kinase pathways. The system will consist of nanoparticles containing Cu/Zn superoxide dismutase, a superoxide scavenger, and fasudil, a Rho-kinase inhibitor and potent vasodilator. The outer surface of the particles will be coated with a cyclic peptide, CAR (CARSKNKDC), that accumulates preferentially in the hypertensive pulmonary arteries of PAH rats. We have generated compelling preliminary data in support of the central hypothesis of this project, and documented the feasibility of the delivery system in peer-reviewed publications. We will use various cellular, inact organ and rodent models of PAH to generate preclinical data-stepping-stones for development of an efficacious drug therapy - and address an unmet medical need. This work is highly innovative because ligand-equipped inhalable particles containing two drugs will relieve PAH symptoms, eliminate the need for needles and catheters, diminish systemic vasodilation, reverse vascular remodeling, attenuate right heart dysfunction, ease economic burdens, free patients from discomfort, and improve quality of life. The investigative team, comprising experts from pharmaceutical, biomedical, chemical, and clinical fields, is highly qualified to conduct the proposed studies. Our long-term goal is to translate this formulation from bench to bedside and develop an effective therapy, which would transform the current treatment modalities for PAH.